Abstract
Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels. However, because of the deficiency of iron regulatory elements (IRE) in FtMt’s gene sequence, the exact function of FtMt remains unclear. In the present study, we found that FtMt dramatically inhibited SH-SY5Y cell proliferation and tumor growth in nude mice. Interestingly, excess FtMt did not adversely affect the development of drosophila. Additionally, we found that the expression of FtMt in human normal brain tissue was significantly higher than that of neuroblastoma, but not higher than that of neurospongioma. However, the expression of transferrin receptor 1 is completely opposite. We therefore hypothesized that increased expression of FtMt may negatively affect the vitality of neuronal tumor cells. Therefore, we further investigated the underlying mechanisms of FtMt’s inhibitory effects on neuronal tumor cell proliferation. As expected, FtMt overexpression disturbed the iron homeostasis of tumor cells and significantly downregulated the expression of proliferating cell nuclear antigen. Moreover, FtMt affected cell cycle, causing G1/S arrest by modifying the expression of cyclinD1, cyclinE, Cdk2, Cdk4 and p21. Remarkably, FtMt strongly upregulated the expression of the tumor suppressors, p53 and N-myc downstream-regulated gene-1 (NDRG1), but dramatically decreased C-myc, N-myc and p-Rb levels. This study demonstrates for the first time a new role and mechanism for FtMt in the regulation of cell cycle. We thus propose FtMt as a new candidate target for inhibiting neuronal tumor cell proliferation. Appropriate regulation of FtMt expression may prevent tumor cell growth. Our study may provide a new strategy for neuronal cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-014-1730-0) contains supplementary material, which is available to authorized users.
Highlights
Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels
Introduction molecules whose expression are affected by Fe depletion include p53, proliferating cell nuclear antigen (PCNA), cyclindependent kinases (Cdks), p21CIP1/WAF1 and hypoxia-inducible factor-1a (HIF1a), which all take part in cell cycle regulation
The negative correlation between transferrin receptor 1 (TfR1) and FtMt may suggest that FtMt plays an important role in iron metabolism and cancer cell proliferation
Summary
Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels. We found that FtMt dramatically inhibited SH-SY5Y cell proliferation and tumor growth in nude mice. We propose FtMt as a new candidate target for inhibiting neuronal tumor cell proliferation. Appropriate regulation of FtMt expression may prevent tumor cell growth. Introduction molecules whose expression are affected by Fe depletion include p53, proliferating cell nuclear antigen (PCNA), Cdks, p21CIP1/WAF1 and hypoxia-inducible factor-1a (HIF1a), which all take part in cell cycle regulation. Our previous studies and those of others have shown that FtMt is involved in the regulation of oxidative stress [18, 19], but little is known about its exact function, especially in tumor tissue. We conclude that FtMt may be explored as a new target for inhibiting the proliferation of neuronal tumors
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